Systemically active drugs have been administered by a wide variety of routes, such as orally, rectally, vaginally, subcutaneously, intramuscularly, intravenously, etc.
Some pharmaceuticals, peptide drugs in particular, are not suitable for oral administration. For these drugs, parenteral administration is the only alternative.
The traditional mode of administration of insulin is by subcutaneous injection. Control of diabetes mellitus often requires multiple injections each day, which are painful and distressing to many patients.
Discomfort and destruction of lifestyle often deter diabetics from accepting intensive insulin treatment. For these reasons, attention has been focused on alternative routes of administration of insulin and other chronically-needed medicaments.
Attempts have been initiated to administer insulin enterally, with and without liposome encapsulation, vaginally, and through the respiratory epithelium. Because of the limited absorption of insulin, these attempts have largely failed.
A great deal of interest has been focused on the intranasal mode of administration of drugs. Vasopressin, luteinizing hormone releasing factor ("LHRF"), adrenocorticotrophic hormone ("ACTH"), and in particular insulin, have been administered intranasally. While intranasal administration offers advantages over other routes, many drugs exhibit only limited absorption through the nasal mucosa. For example, insulin, when administered intranasally, neither increases serum insulin levels nor lowers blood glucose concentration. To be absorbed from the nasal mucosa to reach the blood circulation, the pharmaceutical molecules must be transported across nasal mucous membranes by means of an absorption enhancer.
Many agents have been suggested as intranasal absorption enhancers. U.S. Pat. No. 4,476,116 discloses pharmaceutical compositions for intranasal delivery including chelating agents which enhance absorption across the nasal mucous membranes. U.S. Pat. No. 4,153,689 discloses insulin preparations for intranasal administration containing one or more non-ionic surface-active agents as an absorption enhancer. Bile salts such as sodium deoxycholate have also been used to increase intranasal insulin absorption. Moses et al., Diabetes 32:1040-1047 (1983); Gordon et al., Proc. Natl. Acad. Sci. USA 82:7419 (1985). However, bile salts are undesirable since they cause nasal irritation and damage to the nasal mucosa. While much attention has been devoted to intranasal insulin formulations containing non-ionic surfactant enhancers such as laureth-9 (polyoxethylene-9-laurylether), such surfactants cause nasal stinging, congestion and rhinorrhea. Salzman et al., N. Eno. J. Med. 312:1078-1084 (1985).
What is needed is an effective enhancing agent for the transport of pharmaceutically active substances across the nasal membrane which is free of the irritation and other undesirable side effects experienced with presentlyused intranasal delivery formulations.